Currently, there are no effective treatments for cocaine overdose and it is responsible for more serious intoxications and deaths than any other illicit drug. Previous attempts to develop pharmacotherapies to treat cocaine overdose have been met by one unsuccessful attempt after another. Finally, we have identified a group of drugs that can prevent cocaine-induced behavioral toxicity, under rigorous in vivo conditions, such as would exist in an emergency room. All of our compounds were designed to target sigma receptors, a known binding site for cocaine. Our preliminary studies in mice reveal that over a dozen of our compounds prevent cocaine-induced convulsions and lethality, with up to 100 percent of treated mice surviving a normally fatal overdose. Our best compound even prevents death when administered after an overdose. To our knowledge, no other drug has been reported to be as safe and effective against the toxic effects of cocaine. Initial studies also show that our novel compounds dramatically attenuate the locomotor stimulatory effects of cocaine, indicating that they have the ability to mitigate the actions of cocaine across a range of functional systems. Our preliminary studies provide compelling evidence for the potential therapeutic significance of our novel compounds, and suggest that sigma receptors represent viable, but relatively unrecognized, substrates for the development of anti-cocaine agents. Therefore, the studies in this proposal utilize a multidisciplinary approach to: 1) identify the sigma receptor subtypes that mediate the anti-cocaine actions, 2) evaluate the specificity of the anti-cocaine agents for sigma receptors, 3) identify the areas of the brain that are involved, and 4) determine whether sigma receptors influence the local anesthetic effects of cocaine. Together, we anticipate that these studies will lead to the development of new and effective agents for the treatment of cocaine overdose and addiction.